CCL23 suppresses liver cancer progression through the CCR1/AKT/ESR1 feedback loop.

Abstract

With the ability to activate certain signaling pathways, chemokines and their receptors may facilitate tumor progression at key steps, including proliferation, immunomodulation, and metastasis. Nevertheless, their prognostic value and regulatory mechanism warrant thorough studies in liver cancer. Here, by screening the expression profiles of all known chemokines in independent liver cancer cohorts, we found that CCL23 was frequently downregulated at mRNA and protein levels in liver cancer. Decreased CCL23 correlated with shortened patient survival, enrichment of signatures related to cancer stem cell property, and metastatic potential. In addition to serving as a tumor suppressor through recruiting CD8+ T cell infiltration in liver cancer, CCL23 could repress cancer cell proliferation, stemness, and mobility. Mechanistically, the expression of CCL23 was transcriptionally regulated by ESR1. On the other hand, CCL23 could suppress the activation of AKT signaling and thus promote the expression of ESR1, forming a feedback loop in liver cancer cells. Collectively, these findings reveal that loss of CCL23 drives liver cancer progression by coordinating immune evasion and metastasis initiation. Targeting the ESR1/CCL23/CCR1/AKT regulatory axis could be an effective therapeutic strategy.

• Authors: Jin Meng, Lianghai Wang, Jun Hou, Xiaofeng Yang, Ke Lin, Hongxing Nan, Man Li, Xiangwei Wu, Xueling Chen
• Journal: Cancer science (Cancer Sci) Vol. 112 Issue 8 Pg. 3099-3110 (Aug 2021) ISSN: 1349-7006 [Electronic] England
• PMID: 34050704 (Publication Type: Journal Article)
• Copyright: © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• CCL23 protein, human
• CCR1 protein, human
• Chemokines, CC
• ESR1 protein, human
• Estrogen Receptor alpha
• Receptors, CCR1
• AKT1 protein, human
• Proto-Oncogene Proteins c-akt

Topics

• Cell Line, Tumor
• Cell Proliferation
• Chemokines, CC (genetics, metabolism)
• Disease Progression
• Down-Regulation
• Estrogen Receptor alpha (metabolism)
• Feedback, Physiological
• Gene Expression Regulation, Neoplastic
• Hep G2 Cells
• Humans
• Liver Neoplasms (metabolism, pathology)
• Neoplasm Grading
• Prognosis
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, CCR1 (metabolism)
• Survival Analysis